Jean Y. Tang, MD PhD

Associate Professor of Dermatology at the Stanford University Medical Center

Bio

Bio

Jean Tang, M.D., Ph.D., is an Associate Professor of Dermatology. Dr Tang's research focuses on genetic skin diseases such as Basal Cell Nevus Syndrome and Epidermolysis Bullosa clinical trials. She studies new ways to treat and prevent NSMC and melanoma, and the relationship between sun protection and vitamin D. She conducts preclinical studies in mice, clinical trials in high risk patients and also conducts secondary data analysis using large national datasets. Dr. Tang has led or co-led the conduct and completion of 4 investigator initiated clinical trials with 3 trials focused on BCC cancer treatment and/or prevention. She received her MD/PhD from Stanford, completed her dermatology residency at Stanford, and then went to UCSF for a 3 year post-doc in mouse genetics, while simultaneously pursuing formal coursework in biostatistics, epidemiology, and clinical trial design in the KL2 CTSI program.

Our lab uses mouse models of skin cancer, epidemiology, clinical trials and next gen sequencing methods to identify and test new therapeutics especially for orphan diseases such as Basal Cell Nevus Syndrome (where patients have hundreds of BCC tumors) and patients with Epidermolysis Bullosa who have no treatment.

Clinical Trials

Neurokinin-1 Receptor Antagonist for the Treatment of Itch in EB PatientsNot Recruiting

Our goal is to determine whether daily oral administration of VPD-737 (5 mg) is effective and
safe in adolescents and adults with Epidermolysis Bullosa (EB).

This pilot clinical trial studies how well arsenic trioxide and itraconazole work in treating
patients with basal cell cancer that has spread to other places in the body and usually
cannot be cured or controlled with treatment. Drugs used in chemotherapy, such as arsenic
trioxide, work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Itraconazole may
help treat fungal infections in patients with basal cell cancer. Giving arsenic trioxide with
itraconazole may work better in treating basal cell cancer.

Stanford is currently not accepting patients for this trial.For more information, please contact Irene Bailey-Healy, 408-892-7261.

BCCs are the most common human cancer in the US and affect over 1 million people. There is no
effective drug to prevent basal cell carcinomas of the skin.
We hope to learn if an oral antifungal drug, Itraconazole, might inhibit a marker of
proliferation and a biomarker (tumor signaling pathway) of BCC development.
Itraconazole is an FDA-approved drug for the treatment of fungal infections of the skin, and
has been used for the past 25 years with relatively few side effects. It has been shown in
mice to reduce a BCC biomarker and to reduce growth of BCCs.
Thus, it may reduce BCC growth in humans.

Stanford is currently not accepting patients for this trial.For more information, please contact Jean Tang, (650) 721 - 7152.

Recessive dystrophic epidermolysis bullosa (RDEB) is a disease caused by genetic mutations in
the gene for type VII collagen. Patients with RDEB develop large, severely painful blisters
and open wounds from minor trauma to their skin. We are screening subjects with RDEB to
evaluate characteristics of the subjects and their cells in order to develop new strategies
of therapy and determine whether subjects could be candidates for treatment studies.

Pilot Trial to Evaluate the Effect of Vitamin D on Melanocyte BiomarkersNot Recruiting

The purpose of this study is to determine the signaling pathways and changes in gene
expression in melanocytes of subjects with a history of non-melanoma skin cancer who are
exposed to oral vitamin D. If vitamin D is found to inhibit a signaling pathway involved in
the development of melanoma such as BRAF, a protein involved in cell proliferation, then oral
vitamin D could be explored further as a chemoprevention for melanoma skin cancer.

Stanford is currently not accepting patients for this trial.For more information, please contact Irene Bailey, 650-498-7061.

A Study of FCX-007 for Recessive Dystrophic Epidermolysis Bullosa (RDEB)Recruiting

The purpose of this study is to evaluate the safety of FCX-007, evaluate C7 expression and
the presence of anchoring fibrils resulting from FCX-007 and to analyze wound healing as a
result of FCX-007 administration in subjects with RDEB.

This trial will create a skin graft, which the investigators call "LEAES," using the
patient's own skin cells that have been genetically engineered in the lab to express a
missing protein called type VII collagen. The corrected cells will be transplanted back to
the patient.

Stanford is currently not accepting patients for this trial.For more information, please contact Yana Dutt-Singkh, 650-721-7166.

All Publications

Abstract

Basal cell cancers (BCCs) are characterized by up-regulation of Hedgehog pathway through loss of Patched1 or activation of Smoothened, and smoothened-inhibitors such as vismodegib are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with Basal Cell Nevus Syndrome (BCNS) harbor germline defects in Patched1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to Smoothened-inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low-tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high-burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS-BCCs have a significantly lower mutational load, lower proportion of ultraviolet mutagenesis, increased genomic stability, and harbor fewer functionally resistant Smoothened mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to Smoothened-inhibitors. BCNS-BCCs appear to have reduced mutator phenotype as compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy.

Abstract

Aberrant hedgehog signalling underlies the development of basal-cell carcinomas. We previously reported the interim analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial in patients with the basal-cell nevus (Gorlin) syndrome indicating that the smoothened inhibitor vismodegib reduces basal-cell carcinoma tumour burden and prevents new basal-cell carcinoma growth in patients with basal-cell nevus syndrome. We report the final results of this 36 month trial.In our multicentre, randomised, double-blind, placebo-controlled, phase 2 trial we enrolled patients aged 35-75 years with basal-cell nevus syndrome with at least ten surgically eligible basal-cell carcinomas at the Children's Hospital Oakland, Columbia University outpatient dermatology clinic (NY, USA) and a private practice outpatient dermatology office in Newport Beach (CA, USA). Patients were assigned to vismodegib or placebo (2:1) according to a randomisation sequence generated by computer code. The primary endpoint of the trial of 41 patients was to compare the effect of oral vismodegib (150 mg/day) versus placebo on the incidence of new surgically eligible basal-cell carcinomas after 3 months of treatment. In the subsequent, open-label phase (n=37) patients continued vismodegib at two sites for as long as month 36 (n=25) and at the third site were monitored up to month 36 (n=12). Additional endpoints for this phase were: whether continuous versus interrupted dosing differentially affected tumour burden; time to reach various levels of reduction in tumour burden; reduction in tumour size in patients who took less than 50% of the expected number of vismodegib tablets; reduction in the number of surgical excisions required per year before, during, and after treatment; and the effect of vismodegib on hedgehog target gene expression. We monitored patients at visits every 3 months for up to 36 months. The primary endpoint was analysed on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00957229.Between Sept 22, 2009, and Jan 24, 2011, 41 patients were monitored for a median of 36 months (IQR 36-36). Patients treated with vismodegib (n=26) had a mean reduced rate of new surgically eligible basal-cell carcinomas compared with patients randomly assigned to placebo (n=15; two [SD 0·12] new surgically eligible basal-cell carcinomas per patient per year vs 34 [1·32] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). In the 11 patients initially assigned to placebo, mean cross over to vismodegib reduced the development of new surgically eligible basal-cell carcinomas compared with placebo (0·4 [SD 0·2] new surgically eligible basal-cell carcinomas per patient per year vs 30·0 [7·8] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). Only three (17%) of 18 patients tolerated vismodegib continuously for the full 36 months. Fewer new surgically eligible basal-cell carcinomas developed in patients receiving vismodegib continuously than in those who interrupted dosing (mean 0·6 [0·72] new surgically eligible basal-cell carcinomas per patient per year vs 1·7 [1·8] new surgically eligible basal-cell carcinomas per patient per year, p<0·0001). Treatment-related grade 3-4 adverse events included weight loss of 20% or more (n=6) and muscle cramps (n=2). Two patients died during the course of the trial, one each from laryngeal and metastatic prostate cancer, deemed probably unrelated to drug.Vismodegib reduces basal-cell carcinoma tumour burden in patients with basal-cell nevus syndrome. Adverse events associated with vismodegib frequently led to interruption of treatment, which is followed by basal-cell carcinoma recurrence.Genentech investigator-initiated trial funding, Clinical and Translational Science Award from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, Damon Runyon Cancer Research Foundation Clinical Investigator Award, Swim across America Foundation, and Michael J Rainen Family Foundation.

Abstract

Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

Abstract

Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors.Patients with ≥ one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors.A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size.Itraconazole has anti-BCC activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other HH pathway inhibitors.

Abstract

Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas.We tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas.In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas.Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).

Abstract

An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single-nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR) = 1.06, p = 3.16 × 10(-7) and rs79824801 at 12q13.3: OR = 1.10, p = 1.88 × 10(-5) ) for the first time as independently related to BCC risk in meta-analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR = 1.12, p = 3.99 × 10(-18) ). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC.

Abstract

Across cancers, the decision to pursue genetic testing is influenced more by subjective than objective factors. However, skin cancer, which is more prevalent, visual, and multifactorial than many other malignancies, may offer different motivations for pursuing such testing.The primary objective was to determine factors influencing the decision to receive genetic testing for skin cancer risk. A secondary objective was to assess the impact of priming with health questions on the decision to receive testing.We distributed anonymous online surveys through ResearchMatch.org to assess participant health, demographics, motivations, and interest in pursuing genetic testing for skin cancer risk. Two surveys with identical questions but different question ordering were used to assess the secondary objective.We received 3783 responses (64% response rate), and 85.8% desired testing. Subjective factors, including curiosity, perceptions of skin cancer, and anxiety, were the most statistically significant determinants of the decision to pursue testing (P

Abstract

Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Ɩ/ʎ (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.

Abstract

The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

Abstract

Statins are one of the most widely prescribed drug classes in the USA. This review aims to summarize recent research on the relationship between statin use and cancer outcomes, in the context of clinical guidelines for statin use in patients with cancer or who are at high risk for cancer.A growing body of research has investigated the relationship between statins and cancer with mixed results. Cancer incidence has been more extensively studied than cancer survival, though results are inconsistent as some large meta-analyses have not found an association, while other studies have reported improved cancer outcomes with the use of statins. Additionally, two large studies reported increased all-cancer survival with statin use. Studies on specific cancer types in relation to cancer use have also been mixed, though the most promising results appear to be found in gastrointestinal cancers. Few studies have reported an increased risk of cancer incidence or decreased survival with statin use, though this type of association has been more commonly reported for cutaneous cancers. The overall literature on statins in relation to cancer incidence and survival is mixed, and additional research is warranted before any changes in clinical guidelines can be recommended. Future research areas include randomized controlled trials, studies on specific cancer types in relation to statin use, studies on populations without clinical indication for statins, elucidation of underlying biological mechanisms, and investigation of different statin types. However, studies seem to suggest that statins may be protective and are not likely to be harmful in the setting of cancer, suggesting that cancer patients who already take statins should not have this medication discontinued.

Abstract

We report the first fully automated detection of basal cell carcinoma (BCC), the most commonly occurring type of skin cancer, in human skin using polarization-sensitive optical coherence tomography (PS-OCT). Our proposed automated procedure entails building a machine-learning based classifier by extracting image features from the two complementary image contrasts offered by PS-OCT, intensity and phase retardation (PR), and selecting a subset of features that yields a classifier with the highest accuracy. Our classifier achieved 95.4% sensitivity and specificity, validated by leave-one-patient-out cross validation (LOPOCV), in detecting BCC in human skin samples collected from 42 patients. Moreover, we show the superiority of our classifier over the best possible classifier based on features extracted from intensity-only data, which demonstrates the significance of PR data in detecting BCC.

Abstract

This study aims to investigate the association between statin use and all-cancer survival in a prospective cohort of postmenopausal women, using data from the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT).The WHI study enrolled women aged 50-79 years from 1993 to 1998 at 40 US clinical centres. Among 146 326 participants with median 14.6 follow-up years, 23 067 incident cancers and 3152 cancer deaths were observed. Multivariable-adjusted Cox proportional hazards models were used to investigate the relationship between statin use and cancer survival.Compared with never-users, current statin use was associated with significantly lower risk of cancer death (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.71-0.86, P<0.001) and all-cause mortality (HR, 0.80; 95% CI, 0.74-0.88). Use of other lipid-lowering medications was also associated with increased cancer survival (P-interaction (int)=0.57). The lower risk of cancer death was not dependent on statin potency (P-int=0.22), lipophilicity/hydrophilicity (P-int=0.43), type (P-int=0.34) or duration (P-int=0.33). However, past statin users were not at lower risk of cancer death compared with never-users (HR, 1.06; 95% CI, 0.85-1.33); in addition, statin use was not associated with a reduction of overall cancer incidence despite its effect on survival (HR, 0.96; 95% CI, 0.92-1.001).In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death, regardless of the type, duration, or potency of statin medications used.British Journal of Cancer advance online publication, 9 June 2016; doi:10.1038/bjc.2016.149 www.bjcancer.com.

Abstract

Sun exposure is a major risk factor for skin cancer; however, the relative contribution of ultraviolet (UV) exposure during childhood versus adulthood on skin cancer risk remains unclear.Our goal was to determine the impact of residential UV, measured by AVerage daily total GLObal solar radiation (AVGLO), exposure during childhood (birth, 15 years) versus adulthood (35, 50 years, and present) on incident non-melanoma skin cancer (NMSC) and malignant melanoma (MM) in postmenopausal women.Women were followed with yearly surveys throughout the duration of their participation in the Women's Health Initiative Observational study, a multicenter study from 1993 to 2005. A total of 56,557 women had data on all observations and were included in the baseline characteristics. The main exposure, residential UV (as measured by AVGLO), was measured by geographic residence during childhood and adulthood. Outcome was risk of incident NMSC and MM.Over 11.9 years (median follow-up), there were 9,195 (16.3 %) cases of NMSC and 518 (0.92 %) cases of MM. Compared with the reference group (women with low childhood and low adulthood UV), women with low childhood and high adulthood UV had a 21 % increased risk of NMSC (odds ratio 1.21, 95 % confidence interval 1.12, 1.31). Women with high childhood and high adulthood UV had a 19 % increased risk of NMSC (odds ratio 1.19, 95 % confidence interval 1.11, 1.27). Surprisingly, women with high childhood UV and low adulthood UV did not have a significant increase in NMSC risk compared with the reference group (odds ratio 1.08, 95 % confidence interval 0.91, 1.28) in multivariable models. Residential UV exposure in childhood or adulthood was not associated with increased melanoma risk.This study reveals an increase in NMSC risk associated with adulthood residential UV exposure, with no effect for childhood UV exposure.

Abstract

Phenotypic traits, such as red hair and freckling, increase melanoma risk by 2- to 3-fold. In addition, approximately 10% of melanomas are caused by inherited germline mutations that increase melanoma risk from 4- to >1000-fold. This review highlights the key genes responsible for inherited melanoma, with an emphasis on when a patient should undergo genetic testing. Many genetic syndromes associated with increased melanoma risk are also associated with an increased risk of other cancers. Identification of these high-risk patients is essential for preventive behavior reinforcement, genetic counseling, and ensuring other required cancer screenings.

Abstract

Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease.

Abstract

Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.

Abstract

Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 μm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs.

Abstract

This study aims to determine whether vitamin D levels are associated with menopause-related symptoms in older women.A randomly selected subset of 1,407 women, among 26,104 potentially eligible participants of the Women's Health Initiative Calcium and Vitamin D trial of postmenopausal women aged 51 to 80 years, had 25-hydroxyvitamin D [25(OH)D] levels measured at the Women's Health Initiative Calcium and Vitamin D trial baseline visit. Information about menopause-related symptoms at baseline was obtained by questionnaire and included overall number of symptoms and composite measures of sleep disturbance, emotional well-being, and energy/fatigue, as well as individual symptoms. After exclusions for missing data, 530 women (mean [SD] age, 66.2 [6.8] y) were included in these analyses.Borderline significant associations between 25(OH)D levels and total number of menopausal symptoms were observed (with P values ranging from 0.05 to 0.06 for fully adjusted models); however, the effect was clinically insignificant and disappeared with correction for multiple testing. No associations between 25(OH)D levels and composite measures of sleep disturbance, emotional well-being, or energy/fatigue were observed (P's > 0.10 for fully adjusted models).There is no evidence for a clinically important association between serum 25(OH)D levels and menopause-related symptoms in postmenopausal women.

Abstract

Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis.We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant vismodegib.This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability.Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 4±2 months of vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, vismodegib reduced the surgical defect area by 27% (95% confidence interval -45.7% to -7.9%; P=.006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery.Short follow-up time and no placebo control are limitations.Neoadjuvant vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.

Abstract

The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risks of cancers at several sites in some studies; however, we recently reported no association between their use and total cancer risk in women in a prospective study. Here we examine the association between NSAIDs and total and site-specific cancer incidence in the large, prospective Women's Health Initiative (WHI). Women (129,013) were recruited to participate in the WHI at 40 US clinical centers from 1993 to 1998 and followed prospectively. After 9.7 years of follow-up, 12,998 incident, first primary, invasive cancers were diagnosed. NSAID use was systematically collected at study visits. We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs use and total and site-specific cancer risk. Relative to non-use, consistent use (i.e., use at baseline and year 3 of follow-up) of any NSAID was not associated with total cancer risk (HR 1.00, 95% CI: 0.94-1.06). Results for individual NSAIDs were similar to the aggregate measure. In site-specific analyses, NSAIDs were associated with reduced risks of colorectal cancer, ovarian cancer, and melanoma. Our study confirms a chemopreventive benefit for colorectal cancer in women and gives preliminary evidence for a reduction of the risk of some rarer cancers. NSAIDs' benefit on cancer risk was therefore limited to specific sites and not evident when total cancer risk was examined. This information may be of importance when NSAIDs are considered as chemopreventive agents.

Abstract

Laser therapies have been Food and Drug Administration approved for temporary nail plate clearance; however, there is minimal evidence of their long-term efficacy.We sought to evaluate the clinical and mycological clearance of toenails treated with 1064-nm neodymium:yttrium-aluminum-garnet laser versus no treatment.This was a randomized, controlled, single-center trial comparing 2 treatments with 1064-nm neodymium:yttrium-aluminum-garnet laser (fluence of 5 J/cm(2), rate of 6 Hz) spaced 2 weeks apart versus no treatment in 27 patients (N = 125 affected nails) with clinical and mycological diagnosis of onychomycosis. At 3 months, patients were assessed with mycological cultures and proximal nail plate measurements. Patients treated with laser were also assessed with proximal nail plate measurements at 12 months.At 3 months, 33% of patients treated with laser achieved a negative mycological culture compared with 20% of the control group (P = .49), and had more proximal nail plate clearance compared with control subjects (0.44 vs 0.15 mm, P = .18), which was not statistically significant. At 12 months, there was no difference in nail plate clearance between laser versus control subjects (0.24 vs 0.15 mm, P = .59).Our study was limited by the small sample size and number of treatments.There was no significant mycological culture or clinical nail plate clearance with 1064-nm neodymium:yttrium-aluminum-garnet laser compared with control.

Abstract

Basal cell carcinoma (BCC) is the most common cancer with 2 million treatments per year with little evidence-based guidelines for treatment. There are three classes of interventions (surgical, destructive, and topical) for BCC, and this study aimed to determine whether there are preferences or avoidances in comparisons of different types of treatments for BCC in randomized controlled trials (RCTs).PubMed, Cochrane Central Registry of Clinical Trials, and ClinicalTrials.Gov were used to identify eligible published and registered ongoing RCTs.Fifty-five trials (42 published and 13 registered trials) were identified. Only one unpublished registered trial compared a topical vs. a surgical intervention, and only one trial compared a topical vs. a destructive intervention. Conversely, 44 of the 55 trials compared interventions within the same treatment class and 9 of 55 trials compared surgical vs. destructive interventions. In most trials, selection of same-class comparators was not necessitated by the type of BCC lesions (nonaggressive superficial or nodular vs. aggressive, infiltrative, morpheic BCCs, P = 0.155) or their location (face vs. nonfacial, P = 0.137).This is the first time that an evaluation of network geometry is applied to address issues of comparisons between different families of interventions that belong to different specialties and practices (medical vs. surgical). Previous evaluations of homophily have addressed different families of interventions, in which all interventions are medical (drugs) and performed in the same health-care settings. The noncommunicating bodies of evidence between medical and surgical interventions that we document highlight a problem of unnecessary sequestration of the evidence and the corresponding health-care practices.

Abstract

The relationship between alcohol consumption and preference of alcohol type with hazard of melanoma (MM) and risk of non-melanoma skin cancer (NMSC) was examined in the Women's Health Initiative (WHI) Observational Study (OS).A prospective cohort of 59,575 White postmenopausal women in the WHI OS (mean age 63.6) was analyzed. Cox proportional hazards models and logistic regression techniques were used to assess the hazard and risk of physician-adjudicated MM and self-reported NMSC, respectively, after adjusting for potential confounders including measures of sun exposure and skin type.Over 10.2 mean years of follow-up, 532 MM cases and 9,593 NMSC cases occurred. A significant relationship between amount of alcohol consumed and both MM and NMSC was observed, with those who consume 7+ drinks per week having a higher hazard of MM (HR 1.64 (1.09, 2.49), p global = 0.0013) and higher risk of NMSC (OR 1.23 (1.11, 1.36), p global

Abstract

The relationship between food and environmental allergens in contributing to eczema risk is unclear on a multiethnic population level. Our purpose was to determine whether sensitization to specific dietary and environmental allergens as measured according to higher specific immunoglobulin E (IgE) levels is associated with eczema risk in children. National Health and Nutrition Examination Survey participants ages 1 to 17 years were asked whether they had ever received a diagnosis of eczema from a physician (n = 538). Total and specific serum IgE levels for four dietary allergens (egg, cow's milk, peanut, and shrimp) and five environmental allergens (dust mite, cat, dog, Aspergillus, and Alternaria) were measured. Logistic regression was used to examine the association between eczema and IgE levels. In the United States, 10.4 million children (15.6%) have a history of eczema. Eczema was more common in black children (p < 0.001) and in children from families with higher income and education (p = 0.01). The median total IgE levels were higher in children with a history of eczema than in those without (66.4 vs 50.6 kU/L, p = 0.004). In multivariate analysis adjusted for age, race, sex, family income, household education, and physician-diagnosed asthma, eczema was significantly associated with sensitization to cat dander (odds ratio [OR] = 1.2, 95% confidence interval [CI] 1.05, 1.4, p = 0.009) and dog dander (OR = 1.5, 95% CI, 1.2, 1.7, p < 0.001). After correction for multiple comparisons, only sensitization to dog dander remained significant. U.S. children with eczema are most likely to be sensitized to dog dander. Future prospective studies should further explore this relationship.

Abstract

Facial aging involves changes in the facial skeleton and soft tissues. There is limited quantitative data on soft tissue aging of the face.Magnetic resonance imaging (MRI) was used to quantify and compare facial soft tissue loss over time.Two thousand thirty-seven MRI scans from 58 women divided into young, middle-aged, and older groups were screened. A blinded radiologist used MRI to measure the temporal, infraorbital, and medial and lateral cheek areas.The mean thickness of the subcutaneous tissue in the temporal area was 12.3, 8.4, and 8.9 mm in the young, middle-aged, and older groups, respectively (p < .001). A mean difference of 1.6 mm was seen between the young and middle-aged groups and 2.2 mm between the young and older group (p < .001) in the infraorbital area, 3.3 mm between the young and middle-aged groups and 3.2 mm between the young and older group in the medial cheeks (p < .001), and 2.4 mm between the young and middle-aged groups and 2.4 mm between the young and older group in the lateral cheeks (p = .01).Facial soft tissue undergoes significant deterioration over time, with the most dramatic changes between the ages of 30 and 60 in the temporal, infraorbital, and lateral and medial cheek areas. Soft tissue augmentation and volume correction in these areas may be an effective strategy for facial rejuvenation.

Abstract

Numerous transcriptional regulators of neurogenesis have been identified in the developing and adult brain, but how neurogenic fate is programmed at the epigenetic level remains poorly defined. Here, we report that the transcription factor Pax6 directly interacts with the Brg1-containing BAF complex in adult neural progenitors. Deletion of either Brg1 or Pax6 in the subependymal zone (SEZ) causes the progeny of adult neural stem cells to convert to the ependymal lineage within the SEZ while migrating neuroblasts convert to different glial lineages en route to or in the olfactory bulb (OB). Genome-wide analyses reveal that the majority of genes downregulated in the Brg1 null SEZ and OB contain Pax6 binding sites and are also downregulated in Pax6 null SEZ and OB. Downstream of the Pax6-BAF complex, we find that Sox11, Nfib, and Pou3f4 form a transcriptional cross-regulatory network that drives neurogenesis and can convert postnatal glia into neurons. Taken together, elements of our work identify a tripartite effector network activated by Pax6-BAF that programs neuronal fate.

Abstract

Human papillomavirus (HPV) is ubiquitous in skin and has been associated with nonmelanoma skin cancer. Iannacone et al. investigate the role of HPV in basal cell carcinoma (BCC) by assessing the presence of HPV antibodies, HPV DNA in tumors, and the relationship between these two markers and BCC. In contrast to squamous cell carcinoma (SCC), there is no association between HPV and BCC.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased risk of gastric, colorectal, and breast cancer. However, the impact of NSAIDs on the risk of melanoma has been inconsistent. The authors evaluated the association between NSAID use and cutaneous melanoma risk in the Women's Health Initiative (WHI) Observational Study (OS).At study entry, use of aspirin (acetylsalicylic acid [ASA]) and nonaspirin NSAIDs was assessed among 59,806 postmenopausal Caucasian women ages 50 to 79 years. Cox proportional hazards models were constructed after adjusting for participant skin type, sun exposure history, and medical indications for NSAID use among other confounders.During a median follow-up of 12 years, 548 incident melanomas were confirmed by medical review. Women who used ASA had a 21% lower risk of melanoma (hazard ratio, 0.79; 95% confidence interval, 0.63-0.98) relative to nonusers. Increased duration of ASA use (<1 year, 1-4 years, and ≥ 5 years) was associated with an 11% lower risk of melanoma for each categorical increase (Ptrend = .01), and women with ≥ 5 years of use had a 30% lower melanoma risk (hazard ratio, 0.70; 95% confidence interval, 0.55-0.94). In contrast, use of non-ASA NSAIDs and acetaminophen were not associated with melanoma risk.Postmenopausal women who used ASA had a significantly lower risk of melanoma, and longer duration of ASA use was associated with greater protection. Although this study was limited by the observational design and self-report of NSAID use, the findings suggest that ASA may have a chemopreventive effect against the development of melanoma and warrant further clinical investigation.

Abstract

The rising incidence of nonmelanoma skin cancer (NMSC) is well documented, but data are limited on the number of visits and treatment patterns of NMSC in the outpatient setting.To evaluate practice and treatment patterns of NMSC in the United States over the last decade and to characterize differences according to sex, age, race, insurance type, and physician specialty.Adults with an International Classification of Diseases, Ninth Revision, diagnosis of NMSC were included in this cross-sectional survey study of the National Ambulatory Medical Care Survey between 1995 and 2007. Primary outcomes included population-adjusted NMSC visit rates and odds ratios of receiving a procedure for NMSC using logistic regression.Rates of NMSC visits increased between 1995 and 2007. The number of visits was significantly higher in men, particularly those aged 65 and older. Fifty-nine percent of NMSC visits were associated with a procedure, and the individuals associated with that visit were more likely to be male, to be seen by a dermatologist, and to have private-pay insurance.Nonmelanoma skin cancer visit rates increased from 1995 to 2007 and were higher in men than women. Visits to a dermatologist are more likely to be associated with a procedure for NMSC, and there may be discrepancies in treatment patterns based on insurance type and sex.

Abstract

Organ transplant recipients have an increased risk of nonmelanoma skin cancers due to immunosuppressive therapy following transplantation. Use of sunscreen has been shown to reduce this risk.To identify patient and healthcare factors associated with sun-protective behaviours in organ transplant recipients after transplantation with the goal of increasing overall sunscreen use.This study utilized a cross-sectional, retrospective survey from a national sample of 198 organ transplant recipients in the U.S.A. from 2004 to 2008 with no prior diagnosis of skin cancer. The main outcome measures were sunscreen use and sun avoidance before and after transplantation. Frequency of sunscreen use and sun exposure was obtained by self-report on Likert scales ranging from never to always, and these responses were converted to a numerical scale from 0 to 4.Overall sunscreen use increased after transplantation (from a score of 1·4 to 2·1, P < 0·001). Sex, Fitzpatrick skin type, receiving advice to avoid sun from a healthcare provider, and pretransplantation sunscreen use were significantly associated with frequency of post-transplantation sunscreen use in multivariate models. Pretransplantation sun exposure, advice to avoid sun and pretransplantation sunscreen use were significantly associated with sun avoidance post-transplantation.Both patient features and clinician advice are associated with sun-protective behaviours after organ transplantation. These results will help physicians target expanded sun-protection counselling to those patients most in need of such intervention.

Abstract

Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMO(D477G) medulloblastoma.

Abstract

Malignant fibrous histiocytoma (MFH) is a rare and aggressive tumor. Mohs micrographic surgery (MMS) has been reported as an effective treatment, although most cases were published before advances in cytopathologic techniques led to reclassification of many tumors.To evaluate a contemporary cohort of individuals with MFH and analyze management practices.We reviewed all cases of MFH diagnosed at our institution from January 1995 to December 2010, evaluating 839 records to identify 36 patients undergoing management of tumors of the head and neck.Seventeen of the total 36 patients (47%; mean age 67) experienced tumor recurrence, and 10 (28%) developed metastases. Seven of nine patients initially treated with MMS (78%), and 10 of 24 (42%) treated with WLE experienced recurrence (p = .06). Patients treated with MMS had smaller tissue defects after surgery. The mean contemporary recurrence rate of MFH treated with MMS is significantly higher (58.8%) than the cumulative recurrence rate reported before 2000 (7.4%) (p

Abstract

Ultraviolet radiation is a known risk factor for skin cancer and photoaging. Athletes are at high-risk with frequent sun exposure during peak hours of ultraviolet radiation. The aim of this study was to identify attitudes, personal characteristics, and barriers associated with sunscreen use among a high-risk athlete population.A cross-sectional survey study conducted in 290 collegiate athletes from April 2010 to June 2011 at Duke and Stanford Universities.The average athlete spent 4h per day and 10 months per year training outdoors. While 96% agreed that sunscreen helps prevent skin cancer, over 50% never used sunscreen and 75% used sunscreen 3 or fewer days/week. Having a coach or athletic administrator discuss photoprotection was significantly associated with sunscreen use. Predictors of sunscreen use were female gender, sunburns in the last year, belief at risk for skin cancer, knowing someone with skin cancer, and being worried about wrinkles, sun burns, or skin cancer.Continued identification of characteristics and barriers to sunscreen use can lead to targeted interventions and education in this high-risk group of collegiate athletes with early and elevated total lifetime ultraviolet exposure.

Abstract

Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer.

Abstract

Dyer et al. (this issue) assess the risk of new basal cell carcinoma (BCC) in the Veterans Affairs topical tretinoin chemoprevention trial, which included individuals with a history of at least two prior keratinocyte carcinomas. In addition to known risk factors for a future BCC, such as number of prior BCCs, a history of eczema and lower education levels were also associated with greater risk.

Abstract

When skin tumors are exposed to non-thermal, low energy, nanosecond pulsed electric fields (nsPEF), apoptosis is initiated both in vitro and in vivo. This nanoelectroablation therapy has already been proven effective in treating subdermal murine allograft tumors. We wanted to determine if this therapy would be equally effective in the treatment of autochthonous BCC tumors in Ptch1(+/-)K14-Cre-ER p53 fl/fl mice. These tumors are similar to human BCCs in histology [2,20] and in response to drug therapy [19]. We have treated 27 BCCs across 8 mice with either 300 pulses of 300 ns duration or 2700 pulses of 100 ns duration, all at 30 kV/cm and 5-7 pulses per second. Every nsPEF-treated BCC began to shrink within a day after treatment and their initial mean volume of 36 ± 5 (SEM) mm(3) shrunk by 76 ± 3% over the ensuing two weeks. After four weeks, they were 99.8% ablated if the size of the treatment electrode matched the tumor size. If the tumor was larger than the 4mm wide electrode, multiple treatments were needed for complete ablation. Treated tumors were harvested for histological analysis at various times after treatment and exhibited apoptosis markers. Specifically, pyknosis of nuclei was evident as soon as 2 days after nsPEF treatment, and DNA fragmentation as detected via TUNEL staining was also evident post treatment. Nanoelectroablation is effective in triggering apoptosis and remission of radiation-induced BCCs with a single 6 min-long treatment of 2700 pulses.

Abstract

Pachyonychia congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16 or KRT17), which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in KRT6A and KRT16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowsky type) and KRT6B and KRT17 to PC-2 (Jackson-Lawler type).To describe clinical heterogeneity among patients with PC who have genetic mutations in KRT6A and KRT16.In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for patients with PC. All patients reporting here underwent genetic testing and responded to a standardized, validated survey about their PC symptoms. We report results from 89 patients with KRT6A mutations and 68 patients with KRT16 mutations.Patients with PC who have KRT6A and KRT16 mutations display distinct phenotypic differences. Patients with PC-K6a experience earlier onset, more extensive nail disease and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leucokeratosis (P < 0·001), cysts (P < 0·001) and follicular hyperkeratosis (P < 0·001) compared with their PC-K16 counterparts.Phenotypic differences between patients with KRT6A and KRT16 mutations support adoption of a new classification system based on the mutant gene (PC-6a, PC-16) rather than the PC-1 nomenclature.

Abstract

The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.

Abstract

Sun protection is recommended for skin cancer prevention, yet little is known about the role of sun protection on vitamin D levels. Our aim was to investigate the relationship between different types of sun protective behaviors and serum 25(OH)D levels in the general US population.Cross-sectional, nationally representative survey of 5,920 adults aged 18-60 years in the US National Health and Nutrition Examination Survey 2003-2006. We analyzed questionnaire responses on sun protective behaviors: staying in the shade, wearing long sleeves, wearing a hat, using sunscreen and SPF level. Analyses were adjusted for multiple confounders of 25(OH)D levels and stratified by race. Our primary outcome measures were serum 25(OH)D levels (ng/ml) measured by radioimmunoassay and vitamin D deficiency, defined as 25(OH)D levels <20 ng/ml.Staying in the shade and wearing long sleeves were significantly associated with lower 25(OH)D levels. Subjects who reported frequent use of shade on a sunny day had -3.5 ng/ml (p (trend) < 0.001) lower 25(OH)D levels compared to subjects who reported rare use. Subjects who reported frequent use of long sleeves had -2.2 ng/ml (p (trend) = 0.001) lower 25(OH)D levels. These associations were strongest for whites, and did not reach statistical significance among Hispanics or blacks. White participants who reported frequently staying in the shade or wearing long sleeves had double the odds of vitamin D deficiency compared with those who rarely did so. Neither wearing a hat nor using sunscreen was associated with low 25(OH)D levels or vitamin D deficiency.White individuals who protect themselves from the sun by seeking shade or wearing long sleeves may have lower 25(OH)D levels and be at risk for vitamin D deficiency. Frequent sunscreen use does not appear to be linked to vitamin D deficiency in this population.

Abstract

A number of therapies that target components of the Hedgehog signaling pathway currently are in clinical trials. The specific molecules that seem most promising in basal cell carcinoma and a number of other cancers are those that target the Smoothened transmembrane protein. The pivotal phase II trials have been completed on the Smoothened inhibitor known as GDC-0449; five other agents (BMS-833923, LDE225, LEQ506, IPI926, and TAK-441) have also shown promise in animal studies and early clinical trials and have shown some efficacy in a variety of cancers that are affected by the Hedgehog signaling pathway.

Elucidating the Role of Molecular Signaling Pathways in the Tumorigenesis of Basal Cell CarcinomaSEMINARS IN CUTANEOUS MEDICINE AND SURGERYTang, J. Y.2011; 30 (4): S6-S9

Abstract

The Hedgehog signaling pathway has been identified as fundamentally important to normal embryonic development in living organisms ranging from fruit flies to mammals. Postdevelopmentally, it remains active in hair and skin cells. Abnormal activation of components of the Hedgehog pathway--specifically, resulting from mutations in the Patched 1 gene--is associated with the development of basal cell carcinoma, as well as several other cancers, including medulloblastoma. Patched 1 gene mutation has also been identified as the underlying mechanism in most cases of Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome). Research that resulted in the current understanding of the Hedgehog signaling pathway, in turn, led to multiple lines of investigation to discover mechanisms for halting abnormal signaling, in the hope that agents could be developed that could beneficially stop this pathway. To date, several agents have been developed-and some are in clinical trials-that hold promise for improved nonsurgical treatments for patients with Gorlin syndrome and those with locally advanced/metastatic BCCs.

Abstract

Epidermolysis bullosa (EB) is a family of rare, heterogeneous, genetic disorders characterized by fragility of the skin and mucous membranes. Reduced bone mass and fractures have been recognized as complications of generalized forms of EB.We sought to describe the range and to estimate the prevalence of low bone mass in children with generalized EB, and to identify correlates of low bone mass in this population.This was a prospective, observational study of 24 patients with generalized EB. Each patient completed a history, physical examination, laboratory studies, bone age, and x-rays of the lumbar spine. Those aged 6 years and older underwent dual energy x-ray absorptiometry scans of the lumbar spine. Primary outcomes were areal bone mineral density (aBMD) based on chronologic age, bone age, and adjusted for height Z-score. Descriptive statistics were used to summarize results, and linear regression was used to determine factors associated with low aBMD.Mean lumbar spine aBMD Z-scores ± SD were: -2.6 ± 1.4 for chronologic age, -1.7 ± 1.3 for bone age, and -1.0 ± 1.2 after adjusting for height Z-score. aBMD Z-scores were less than or equal to -2 in 64% for chronologic age, 50% for bone age, and 28% after adjusting for height Z-score. aBMD correlated with height Z-score, weight Z-score, extensive blistering, immobility, albumin, hemoglobin, iron, erythrocyte sedimentation rate, and c-reactive protein values.Small sample size was a limitation.Children with severe, generalized recessive dystrophic EB have low aBMD for age. Deficits in aBMD were reduced after adjusting for delayed skeletal maturation and small body size.

Abstract

In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC.Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.

Abstract

Sun protection messages in the United States emphasize sunscreen use, although its efficacy in skin cancer prevention remains controversial.We used data from NHANES 2003-2006, restricted to adult whites (n = 3,052) to evaluate how Americans protect themselves from the sun. Participants completed questionnaires on the frequency with which they used sunscreen, wore a hat, long sleeves, or stayed in the shade, in addition to the number of sunburns in the past year.Although using sunscreen is the most common sun protective behavior (30%), frequent sunscreen use was not associated with fewer sunburns. However, the odds of multiple sunburns were significantly lower in individuals who frequently avoided the sun by seeking shade (OR = 0.70, p < 0.001) or wearing long sleeves (OR = 0.73, p = 0.01).Our findings suggest that shade and protective clothing may be more effective than sunscreen, as typically used by Americans.

Abstract

Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days.In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study.Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.

Abstract

Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC Research Registry is a database with information on patients' symptoms as well as genotypes. We sought to describe the heterogeneity of clinical symptoms and to investigate possible genotype-phenotype correlations in patients with two types of K16 mutations, p.Asn125 and p.Arg127, causing the PC-16 subtype of PC. We found that clinical symptoms depended on the type of amino-acid substitution. Patients with p.Asn125Asp and p.Arg127Pro mutations exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. We speculate that amino-acid substitutions causing larger, more disruptive changes to the K16 protein structure, such as a change in amino-acid charge in the p.Asn125Asp mutation or a bulky proline substitution in the p.Arg127Pro mutation, may also lead to more severe disease phenotypes. The variation in phenotypes seen with different substitutions at the same mutation site suggests a genotype-phenotype correlation. Knowledge of the exact gene defect is likely to assist in predicting disease prognosis and clinical management.

Abstract

Constitutive Hedgehog (HH) signaling underlies several human tumors, including basal cell carcinoma (BCC). Recently, Bijlsma and colleagues reported a new biologic function for vitamin D3 in suppressing HH signaling in an in vitro model system. On the basis of that work, we have assessed effects of vitamin D3 on HH signaling and proliferation of murine BCCs in vitro and in vivo. We find that indeed in BCC cells, vitamin D3 blocks both proliferation and HH signaling as assessed by mRNA expression of the HH target gene Gli1. These effects of vitamin D3 on Gli1 expression and on BCC cell proliferation are comparable to the effects of cyclopamine, a known inhibitor of the HH pathway. These results are specific for vitamin D3, because the precursor 7-dehydrocholesterol and the downstream products 25-hydroxy vitamin D3 [25(OH)D] and 1,25-dihydroxy vitamin D3 [1,25(OH)(2)D] are considerably less effective in reducing either Gli1 mRNA or cellular proliferation. Moreover, these effects seem to be independent of the vitamin D receptor (VDR) because short hairpin RNA knockdown of VDR does not abrogate the anti-HH effects of D3 despite reducing expression of the VDR target gene 24-hydroxylase. Finally, topical vitamin D3 treatment of existing murine BCC tumors significantly decreases Gli1 and Ki67 staining. Thus, topical vitamin D3 acting via its HH inhibiting effect may hold promise as an effective anti-BCC agent.

Abstract

To evaluate vitamin D status in patients with basal cell nevus syndrome (BCNS) who practice photoprotection because of their genetic predisposition to skin cancer and to determine risk factors for deficiency.Retrospective cohort study.Academic medical centers.Forty-one ambulatory patients with BCNS who participated in a 2-year chemoprevention clinical trial. Population-based controls (n = 360) were selected and matched by age, sex, Fitzpatrick skin type, and season/geography.Levels of 25-hydroxyvitamin D (25[OH]D) and vitamin D deficiency (defined as a 25[OH]D level of ≤20 ng/mL).Twenty-three patients with BCNS (56%) were vitamin D deficient. Patients with BCNS had mean 25(OH)D levels below those of the general population (-3 ng/mL; P = .02) and were 3 times more likely to be vitamin D deficient (56% vs 18%; P < .001). Levels of 25(OH)D were lower in patients who were overweight (-3.0 ng/mL; P = .04) and who had blood collected in the winter compared with the summer (-7.1 ng/mL; P < .001). Conclusion: Patients with BCNS may be at increased risk for vitamin D deficiency, depending on their adherence to photoprotection practices.

Abstract

In the United States, the annual incidence of basal cell carcinoma (BCC) is close to 1 million. Ultraviolet radiation exposure is the main risk factor; however, the availability of ever more potent sunscreens and education have not prevented the rise in BCC incidence. Therefore, concerted effects to identify novel preventive and therapeutic strategies are necessary.This article summarizes our current understanding of the etiology and molecular mechanisms of BCC tumorigenesis and discusses the preclinical and clinical studies to identify agents with anti-BCC efficacy.The discovery that hyperactive Hh pathway signaling causes several cancers, including BCC, has spawned the development of many pharmacologic inhibitors of Hh signaling. Early clinical testing of the most advanced, GDC-0449, demonstrated impressive efficacy in patients with advanced BCC. Other promising anti-BCC chemopreventive strategies include drugs that are already FDA-approved for treating other diseases.Preclinical and clinical trials with pre-existing FDA-approved drugs suggest novel uses for BCC chemoprevention and treatment. Also, new chemical entities that inhibit the Hh pathway show promise, and in combination with other drugs may provide a nonsurgical cure for this most common cancer.

Abstract

In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.

Abstract

To determine the relationship between 25(OH) vitamin D levels and non-melanoma skin cancer (NMSC), we performed a nested case-control study in ambulatory, elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study. Health habit and medical history, including self-reported history of NMSC were recorded and 25(OH)D levels were measured on serum collected at baseline from a random sample of Caucasian MrOS subjects. Mean age (73 +/- 5), BMI, daily vitamin D and calcium intake were similar in the men with (n = 178) and without NMSC (n = 930), but higher levels of 25(OH)D were associated with a decreased risk of having a history of NMSC (P(trend) = 0.04). Men in the highest quintile of 25(OH)D (>30 ng/mL) had 47% lower odds of NMSC (95% CI: 0.30-0.93, p = 0.026) compared to those in the lowest quintile. Our results suggest that a diagnosis of NMSC is not a surrogate for adequate 25(OH)D levels or increased UV exposure, and high 25(OH)D levels may be associated with a reduced risk of NMSC.

Abstract

In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.

Abstract

We examined the association between statin use and basal cell carcinoma (BCC) risk.We identified all members of a large integrated health care delivery system with a diagnosis of a histologically proven BCC in 1997. Subsequent BCCs were identified through 2006 from health plan electronic pathology records. Longitudinal exposure to statins and other lipid-lowering agents was determined from automated pharmacy records. We used extended Cox regression to examine the independent association between receipt of statin therapy (ever vs never, cumulative duration) and risk of subsequent BCC. To minimize confounding by indication, we conducted sensitivity analyses in the subset of individuals considered eligible for lipid-lowering therapy based on national guidelines.Among 12,123 members given a diagnosis of BCC who had no prior statin exposure, 6381 developed a subsequent BCC during follow-up. Neither "ever use of statins" (adjusted hazard ratio 1.02, 95% confidence interval: 0.92-1.12) or cumulative duration of statin (adjusted hazard ratio 1.02/year, 95% confidence interval: 0.99-1.11) was associated with subsequent BCC after adjustment for age, sex, and health care use. Risk estimates did not change appreciably when the analysis was limited to the subset of individuals who met eligibility criteria for initiating statin therapy. There was also no significant association between use of non-statin antilipemics and subsequent BCC (adjusted hazard ratio 1.10, 95% confidence interval: 0.76-1.58).No information was available for BCC risk factors, such as sun sensitivity and sun exposure.Among a large cohort of individuals with BCC, statin therapy was not significantly associated with risk of subsequent BCC.

Abstract

The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastrointestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.

Abstract

Toxicity from radiation therapy is a grave problem for cancer patients. We hypothesized that some cases of toxicity are associated with abnormal transcriptional responses to radiation. We used microarrays to measure responses to ionizing and UV radiation in lymphoblastoid cells derived from 14 patients with acute radiation toxicity. The analysis used heterogeneity-associated transformation of the data to account for a clinical outcome arising from more than one underlying cause. To compute the risk of toxicity for each patient, we applied nearest shrunken centroids, a method that identifies and cross-validates predictive genes. Transcriptional responses in 24 genes predicted radiation toxicity in 9 of 14 patients with no false positives among 43 controls (P = 2.2 x 10(-7)). The responses of these nine patients displayed significant heterogeneity. Of the five patients with toxicity and normal responses, two were treated with protocols that proved to be highly toxic. These results may enable physicians to predict toxicity and tailor treatment for individual patients.

Abstract

The c-Abl tyrosine kinase is activated by some forms of DNA damage, including ionizing radiation, but not UV radiation. The functions of this activation in the damage response pathways remain obscure. To identify potential targets of c-Abl kinase, we utilized the yeast two-hybrid system to screen a murine cDNA library. One c-Abl binding protein of particular interest was the large subunit (DDB1) of the heterodimeric complex with UV-damaged DNA binding activity (UV-DDB). This complex binds with high specificity to DNA damaged by UV, is absent in a subset of xeroderma pigmentosum group E cells, and is required for global genomic repair of UV-induced damage. The association of c-Abl with DDB1 required the kinase domain of c-Abl and preserved the interaction between DDB1 and the small subunit (DDB2) of the UV-DDB complex. Significantly, overexpression of c-Abl increased tyrosine phosphorylation of DDB2 and suppressed UV-DDB activity. Conversely, a dominant negative, kinase-deficient allele of c-Abl decreased tyrosine phosphorylation of DDB2 and dramatically stimulated UV-DDB activity. These results suggest that one role of c-Abl may be to negatively regulate UV-DDB activity by phosphorylation of DDB2.

Abstract

UV-damaged DNA-binding protein (UV-DDB) is composed of two subunits, DDB1 (p127) and DDB2 (p48). Mutations in the DDB2 gene inactivate UV-DDB in individuals from complementation group E of xeroderma pigmentosum (XP-E), an autosomal recessive disease characterized by sun sensitivity, severe risk for skin cancer and defective nucleotide excision repair. UV-DDB is also deficient in many rodent tissues, exposing a shortcoming in rodent models for cancer. In vitro, UV-DDB binds to cyclobutane pyrimidine dimers (CPDs), 6-4 photoproducts and other DNA lesions, stimulating the excision of CPDs, and to a lesser extent, of 6-4 photoproducts. In vivo, UV-DDB plays an important role in the p53-dependent response of mammalian cells to DNA damage. When cells are exposed to UV, the resulting accumulation of p53 activates DDB2 transcription, which leads to increased levels of UV-DDB. Binding of UV-DDB to CPDs targets these lesions for global genomic repair, suppressing mutations without affecting UV survival. Apparently, cells are able to survive with unrepaired CPDs because of the activity of bypass DNA polymerases. Finally, there is evidence that UV-DDB may have roles in the cell that are distinct from DNA repair.

Abstract

UV-damaged DNA-binding activity (UV-DDB) is deficient in some xeroderma pigmentosum group E individuals due to mutation of the p48 gene, but its role in DNA repair has been obscure. We found that UV-DDB is also deficient in cell lines and primary tissues from rodents. Transfection of p48 conferred UV-DDB to hamster cells, and enhanced removal of cyclobutane pyrimidine dimers (CPDs) from genomic DNA and from the nontranscribed strand of an expressed gene. Expression of p48 suppressed UV-induced mutations arising from the nontranscribed strand, but had no effect on cellular UV sensitivity. These results define the role of p48 in DNA repair, demonstrate the importance of CPDs in mutagenesis, and suggest how rodent models can be improved to better reflect cancer susceptibility in humans.

Abstract

Experimental evidence suggests that aldehydes generated as a consequence of lipid peroxidation may be involved in the pathogenesis of atherosclerosis. It is well documented that aldehydes modify LDL: however, less is known concerning the effects of aldehydes on other plasma and interstitial fluid components. In the present study, we investigated the effects of five physiologically relevant aldehydes (acetaldehyde, acrolein, hexanal, 4-hydroxynonenal [HNE], and malondialdehyde [MDA]) on two key constituents of the antiatherogenic reverse cholesterol transport pathway, lecithin-cholesterol acyltransferase (LCAT) and HDL. Human plasma was incubated for 3 hours at 37 degrees C with each one of the five aldehydes at concentrations ranging from 0.16 to 84 mmol/L. Dose-dependent decreases in LCAT activity were observed. The short-chain (acrolein) and long-chain (HNE) alpha,beta-unsaturated aldehydes were the most effective LCAT inhibitors. Micromolar concentrations of these unsaturated aldehydes resulted in significant reductions in plasma LCAT activity. The short- and longer-chain saturated aldehydes acetaldehyde and hexanal and the dialdehyde MDA were considerably less effective at inhibiting LCAT than were acrolein and HNE. In addition to inhibiting LCAT, aldehydes increased HDL electrophoretic mobility and cross-linked HDL apolipoproteins. Cross-linking of apolipoproteins A-I and A-II required higher aldehyde concentrations than inhibition of LCAT. The alpha,beta-unsaturated aldehydes acrolein and HNE were fourfold to eightfold more effective cross-linkers of apolipoproteins A-I and A-II than the other aldehydes studied. These data suggest that products of lipid peroxidation, especially unsaturated aldehydes, may interfere with normal HDL cholesterol transport by inhibiting LCAT and modifying HDL apolipoproteins.